The long-term goal of this application is to gain information about mechanisms that control homeostasis of membrane lipids in cells of the nervous system. Such control is critical to ensure normal function and traffic of cellular membranes, and dysfunction of these mechanisms result in neurological and psychiatric diseases. The specific goal of this application is to advance knowledge of lipid transfer reactions that occur at contact sites between the endoplasmic reticulum (ER) and other membranes and that are mediated by membrane tethering proteins containing lipid transport modules of the TULIP domain superfamily. The occurrence of protein- dependent, but membrane traffic-independent, transport of lipids between the ER and other membranes has been known for decades. Recently, however, it has become clear that much of such transport occurs at membrane contact sites. Additionally, several new proteins that localize at membrane contact sites and contain lipid transport modules have been identified. These mechanisms so far have not been investigated in cells of the nervous system, although contacts between the ER and other organelles have been described in all neuronal compartments including synapses. Here I propose to investigate the properties, mechanisms of action and physiological functions of two proteins that function at contacts between the ER and other membranes. The first is TMEM24, an intrinsic ER protein by far preferentially expressed in neurons and neuroendocrine cells. TMEM24 contains a lipid transport module of the TULIP domain superfamily (an SMP domain) and functions as a regulated tether between the ER and the plasma membrane. We hypothesize that the lipid transport function of TMEM24 regulates signaling reactions at the plasma membrane. The second is Vps13A/chorein, a very large protein without transmembrane regions that we have found to be concentrated at ER-mitochondria contacts, where it tethers their membranes. Loss-of-function mutations in Vps13A result in chorea-acanthocytosis, a neurodegenerative condition resembling Huntington's disease with an associated defect of red blood cells. Mutations in a closely related protein, Vps13C, are responsible for a familial form of Parkinson's disease. Based on preliminary results we hypothesize that one function of Vps13A is to mediate lipid transport between the ER and mitochondria via SMP like domains. We will test these hypotheses with a variety of complementary experimental strategies ranging from in vitro reconstitution of lipid transport between artificial liposomes, to studies in cultured cells (including iPS cells) and mutant mice. Results of this research will provide insight into completely unknown aspects of neuronal and synaptic function and into pathogenetic mechanisms in neurodegenerative diseases.